Bisphosphonate-prodrugs

Abstract

The present invention relates to a prodrug, comprising a pharmaceutically and/or diagnostically active compound, and one or more bisphosphonate groups, to a process for producing such a prodrug, and to a pharmaceutical composition comprising said prodrug, to be used for the treatment of bone-related disorders such as bone cancer.

The invention claimed is: 
     
       1. A prodrug, comprising general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         unit (a) represents a pharmaceutically and/or diagnostically active compound, said pharmaceutically and/or diagnostically active compound is a cytostatic agent selected from the group consisting of N-nitrosoureas, the anthracyclines doxorubicin, 2-pyrollinoanthracycline, morpholinoanthracycline, diacetatoxyalkylanthracycline, daunorubicin, epirubicin, idarubicin, mitoxantrone and ametantrone; the alkylating agents chlorambucil, bendamustine, melphalan, and oxazaphosphorines; the antimetabolites 5-fluorouracil, 2′-deoxy-5-fluorouridine, cytarabine, cladribine, fludarabine, pentostatine, gemcitabine, 6-thioguanine and 6-mercaptopurine; the folic acid antagonists methotrexate, raltitrexed, pemetrexed and plevitrexed; the camptothecins topotecan, irinotecan, SN-38, 10-hydroxycamptothecin, GG211, lurtotecan, 9-aminocamptothecin and camptothecin; the Vinca alkaloids vinblastine, vincristine, vindesine and vinorelbine; calicheamicins; maytansinoids; auristatins; epothilones; duocarmycins; bleomycin, dactinomycin, plicamycin, mitomycin C and cis-configured platinum(II) complexes; 
         unit (b) represents a cleavable linker which is directly bound to the pharmaceutically and/or diagnostically active compound, said cleavable linker selected from the group consisting of:
 (i) an enzymatically cleavable peptide sequence selected from the group consisting of -Arg-, -Arg-Arg-, -Phe-Arg-, -Phe-Cit-, -Ile-Pro-Lys-, -Lys-, -Lys-Lys-, -Arg-Lys-, -Leu-Arg-, -Phe-Arg-, -Val-Arg-, -Ala-Leu-Ala-Leu- [SEQ ID NO:1], -Phe-Lys-, -Phe-Lys-Ala-, -Val-Cit-, -Val-Ala-, -Val-Arg-, -Ala-Phe-Lys-, -D-Ala-Phe-Lys-, -Ser-Ser-Tyr-Tyr-Ser-Arg- [SEQ ID NO:2], -Phe-Pro-Lys-Phe-Phe-Ser-Arg-Gln- [SEQ ID NO:3], -Lys-Pro-Ile-Glu-Phe-Nph-Arg-Leu- [SEQ ID NO:4], -Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln- [SEQ ID NO:5], -Gly-Pro-Gln-Gly-Ile-Trp-Gly-Gln- [SEQ ID NO:6], -Gly-Phe-Leu-Gly- [SEQ ID NO:7], -Gly-Gly-, -Gly-Gly-Gly- and -Gly-Gly-Gly-Arg-Arg- [SEQ ID NO:8] 
 (ii) an acid-sensitive group which can be cleaved upon a decrease in the pH-value and which is selected from the croup consisting of ester, acetal, ketal, imine, hydrazone, acylhydrazone and sulfonylhydrazone bonds or bonds containing a trityl group; 
 (iii) the enzymatically cleavable peptide sequence of (i) bound to a self-immolative croup which is selected from the croup consisting of: 
 
       
       
         
           
           
               
               
           
         
         wherein the pharmaceutically and/or diagnostically active compound (a) is bound to the Z-terminus of the self-immolative group, wherein L and Z are independently selected from O, S and NH, and R represents one or more substituents at the phenyl ring which are independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, a C 1-8  alkyl group and a C 1-6  aryl group; or
 (iv) the acid-sensitive group of (iii) bound to a self-immolative group which is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         wherein the pharmaceutically and/or diagnostically active compound (a) is bound to the Z-terminus of the self-immolative group, wherein L and Z are independently selected from O, S and NH, and R represents one or more substituents at the phenyl ring which are independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, a C 1-8  alkyl group and a C 1-6  aryl group; 
         unit (c) represents a spacer group which is directly bound to the cleavable linker, the spacer group selected from the group consisting of a maleinimide—obtained unit, a halogenacetamide—obtained unit, a halogenacetate—obtained unit, a pyridylthio—obtained unit, a vinyl carbonyl—obtained unit, an aziridin—obtained unit, a disulfide—obtained unit, and a substituted or unsubstituted acetylene—obtained unit; and 
         unit (d) represents one or more bisphosphonate groups which are directly bound to the spacer group, the one or more bisphosphonate groups are independently selected from the group consisting of etidronate, clodronate, tiludronate, pamidronate, 1-amino-1,1-diphosphonate methane, risedronate, ibandronate, 1-hydroxy ethylidene-1,1-diphosphonic acid, alendronate and zoledronate, or wherein the one of more bisphosphonate groups (d) are independently one of the following structures (IIa) to (Va), (IIb) to (Vb), (VIa) to (VIIIa) or (VIb) to (VIIIb): 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         o is an integer independently selected from 0 to 12, 
         p is an integer independently selected from 0 to 2, 
         q is an integer independently selected from 0 to 2, 
         r is an integer independently selected from 1 or 2, 
         s is an integer independently selected from 0 to 12, 
         t is an integer independently selected from 0 to 2, 
         u is an integer independently selected from 0 or 1, 
         v is an integer independently selected from 0 to 2, 
         each of X and Y are independently selected from the group consisting of F, Cl, Br, I, NO 2 , SO 3 H 1  CN, OH, COOH, COOCH 3 , —CHO, —CHOCH 3 , an C 1-8  alkyl group and an C 1-6  aryl group, 
         R 1  is the same or different and is independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, COOCH 3 , —CHO, —CHOCH 3 , an C 1-8  alkyl group and an C 1-6  aryl group, 
         E represents O, NH, a carbon-carbon single bond, a carbon-carbon double bond or a carbon-carbon triple bond, and
 M is independently selected from hydrogen, sodium, potassium, calcium and magnesium. 
 
       
     
     
       2. The prodrug according to  claim 1 , wherein an aliphatic chain —(CH 2 ) n — is bound to the spacer group (c) with n being an integer of from 1 to 12, an oligoethylene glycol —(O—CH 2 —CH 2 ) n — with n being an integer of from 1 to 12, or a phenyl ring, optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, NO 2 , SO 3 H, CN, OH, COOH, a C 1-8  alkyl group and a C 1-6  aryl group, or combinations thereof. 
     
     
       3. The prodrug according to  claim 1 , wherein the unit (d) represents the one or more bisphosphonate groups having one of the following structures (IIa) to (Va) or (IIb) to (Vb): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein o, p, q, r, s, t, u, v, X, Y, R 1 , E and M are as defined above. 
       
     
     
       4. The prodrug according to  claim 1 , wherein the unit (d) is selected from one of the following structures (VIa) to (VIIIa) or (VIb) to (VIIIb) 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         R 1  may be the same or different and is independently selected from the group consisting of F, Cl, Br, I, NO 2 , CN, COOCH 3 , —CHO, —CHOCH 3 , an C 1-8  alkyl group and an C 1-6  aryl group, and 
         M is independently selected from hydrogen, sodium, potassium, calcium and magnesium. 
       
     
     
       5. The prodrug according to  claim 3 , wherein the unit (c) is selected from one of the following structures (IX) to (XII): 
       
         
           
           
               
               
           
         
         wherein PEG represents polyethylene glycol), and l, m and n are independently selected from an integer of from 0 to 12. 
       
     
     
       6. The prodrug according to  claim 3 , wherein the units (a) and (b) taken together are selected from one of the following structures (XIII) to (XVII): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       7. A pharmaceutical composition comprising the prodrug according to  claim 1 , and optionally a pharmaceutically acceptable carrier, a pharmaceutically acceptable adjuvant and/or a diluent. 
     
     
       8. A prodrug of formula (6):